A 4,5-epoxymorphinan derivative represented by the Formula (I) (described later) or a pharmacologically acceptable acid addition salt thereof, which is the effective ingredient of the present invention, has prominent antipruritic effect and has been disclosed as a compound effective as a therapeutic drug for pruritus in a variety of diseases accompanying pruritus (for example, see Patent Document 1). However, the aforementioned 4,5-epoxymorphinan derivative has been known to be chemically unstable to light, heat and oxygen, and with regard to the method of stabilizing such 4,5-epoxymorphinan derivative, it is described that a stable pharmaceutical composition can be obtained by allowing the composition to contain a saccharide(s) or sugar alcohol(s) and an antioxidant such as sodium thiosulfate (see Patent Document 2). Yet, when the present inventors examined tableting of the 4,5-epoxymorphinan derivative represented by the Formula (I) or a pharmacologically acceptable acid addition salt thereof, it was revealed that, although a conventionally known stabilization method in which an antioxidant such as sodium thiosulfate is added is effective for stabilization of the effective ingredient in a liquid-form, in cases where the method is employed for a tablet, it is difficult to obtain a tablet whose decomposition is minimized over a long period of time in unpacked state or in a normal package form and which maintains sufficient stability as a tablet.
Conventionally, as a method of stabilizing various morphinan compounds including morphine, a technique of adding a basic component to morphine (for example, see Patent Document 3) and a method in which an antioxidant such as sodium thiosulfate or tocopherol is combined with naloxone (for example, see Patent Document 4), as well as a method in which a chelating agent and a citrate buffer are added to methylnaltrexone (for example, see Patent Document 5) and a method in which an organic acid and a chelate forming agent are blended with naltrexone hydrochloride (for example, see Patent Document 6), have been disclosed. However, none of these reports includes any description with regard to the type and the content of disintegrating agent effective in stabilization, and the stabilization effect imparted to a tablet by a specific disintegrating agent, crospovidone or sodium carboxymethyl starch, has not been revealed.
Meanwhile, as a tablet which comprises a saccharide such as lactose or a sugar alcohol such as mannitol or erythritol and, as disintegrating agent, crospovidone or sodium carboxymethyl starch, an intraorally disintegrating-type tablet which is intended for improving the dose compliance and can be taken without water has been disclosed (for example, see Patent Document 7). However, all of such reports merely disclose a tablet which has superior intraoral quick disintegration property along with formulation strength at a level which does not pose a problem in handling, and the stabilization effect imparted by crospovidone or sodium carboxymethyl starch has not been reported.
In addition, as a method of stabilizing a drug by blending crospovidone or sodium carboxymethyl starch, there are reports that fast release property is attained and drug hydrolysis is suppressed by blending crospovidone with sarpogrelate hydrochloride (see Patent Document 8); that a preparation which has both disintegration property and tablet hardness, as well as excellent storage stability over a long period of time, is attained by blending crospovidone or sodium carboxymethyl starch with iguratimod (see Patent Document 9); and that the stability is improved by blending crospovidone with vitamin or the like (for example, see Patent Document 10 and Non-patent Document 1). However, needless to say, since the mechanism of drug destabilization is largely dependent on the chemical structure and physiochemical properties of the drug, these reports offer no suggestion with regard to the stability of the effective ingredient of the present invention, which is a 4,5-epoxymorphinan derivative represented by the Formula (I) or a pharmacologically acceptable acid addition salt thereof.